Comparative thrombotic risk associated with <scp>CALR1</scp>, <scp>CALR2</scp>, and <scp>JAK2 V617F</scp> mutations in essential thrombocythemia
Authors: Niraj Neupane, Soon K. Low, Himal Kharel, Sanket Bhattarai, Sangharsha Thapa, Amir Mahmoud, Nishant B. Pokhrel, Mohammad Ammad Ud Din, Peter Kouides
Journal: American Journal of Hematology (2023)

Thrombosis is a common complication of Essential Thrombocythemia (ET) and is responsible for significant morbidity and mortality in affected individuals. The JAK2 V617F mutation is a well-established risk factor for thrombosis in ET, with a reported prevalence of approximately 50% in patients with ET. However, there is increasing evidence that other mutations, including CALR mutations, also independently confer increased thrombotic risk in ET. CALR functions as a chaperone protein that screens misfolded proteins in the endoplasmic reticulum and prevents transition to the Golgi apparatus and, ultimately, to the cell surface. CALR mutations are exon 9 frameshift mutations due to 52-base pair deletion in type 1 or 5-base pair insertion in type 2. JAK2 and CALR mutations have been proposed to represent two distinct subtypes of ET due to their significant differences in thrombosis risk and disease progression. Therefore, we conducted a systematic review and meta-analysis comparing the cumulative thrombotic risk between different CALR mutation types (type 1 and type 2), and JAK2 V617F mutation in ET. We searched PubMed, Google Scholar, MEDLINE OVID, Cochrane Library, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases to identify relevant peer-reviewed studies published from database inception to January 2023 without any language restrictions. The overall odds ratio (OR) was computed using the random-effects model to account for the expected heterogeneity among included studies. The meta-analysis included a total of 15 studies.1-15 There were 795 included patients with CALR1 mutations, 561 included patients with CALR2 mutations, and 3538 included patients with JAK2 mutations. Most of the studies were retrospective in design and conducted in different countries. The quality of studies was assessed by the JBI risk assessment tool. Most of the studies (10 out of 15) had a low risk of bias, while others had a moderate risk of bias. The rank correlation test for funnel plot asymmetry did not reveal publication bias. The pooled odds ratios for thrombosis in CALR1 versus JAK2, CALR2 versus JAK2, and CALR1 versus CALR2 were 0.65 (95% confidence interval [CI], 0.46–0.91), 0.45 (95% CI, 0.32–0.62), and 1.50 (95% CI, 1.00–2.24), respectively (Figure 1). Sensitivity analysis was conducted among 8 studies after excluding the medium and high risk of bias studies, which showed pooled odds ratio in CALR1 versus CALR2 and CALR1 versus JAK2 were 1.81 (95% CI of 1.04 to 3.13, p = .03) and 0.6 (95% CI of 0.44 to 0.82), respectively. Subgroup analysis based on the site of thrombosis did not show any statistically significant results except for a lower venous thrombotic risk with CALR2 compared to JAK2. This could be because our analysis was underpowered to detect the differential risk of arterial thrombosis between these patients. Our results suggest that ET patients with CALR1 or CALR2 mutations have a lower risk of thrombosis than those with JAK2 mutations. Moreover, ET patients with CALR1 were found to have a higher risk of thrombosis than those with CALR2. The pathophysiology for the difference is unknown, although it can be speculated that CALR2 mutation will lead to less activation of the thrombopoietin receptors and less ADP-induced platelet activation in light of its lower net positive charge.16 More recently, function of mutant CALR protein as rogue cytokine which functions in a way similar to thrombopoietin has been discovered. However, the association between CALR mutations and thrombotic risk requires further investigation, as the included studies varied in patient populations, study designs, and follow-up periods. In addition, we were unable to stratify the thrombotic events based on their severity or recurrence due to the lack of available data and we could not obtain adequate data on thrombosis-free survival. Our study highlights the need for personalized risk assessment and management strategies for ET patients based on their specific mutation status. The authors received no financial support for the research, authorship, and/or publication of this article. The authors have no conflicts of interest to declare. All the required information is in the manuscript itself.